Cytotoxic effector CD4 T cells express NKG2C/E and are defined by a unique program dependent on Blimp-1. (IRC8P.482)

Abstract

Abstract CD4 T cells with cytotoxic activity can be generated during many immune responses to acute viral infections and they can contribute to CD4-mediated viral control. During the peak of the CD4 T cell response to an acute infection of influenza A/PR8 [IAV], cytotoxic CD4 T cells [ThCTL] are found in the lung. The cytotoxicity they mediate is MHC II-restricted and perforin-dependent. We find the lung ThCTL express NKG2C and E that are members of the killer cell lectin-like receptor family [KLR]. Although the ThCTL cytotoxicity is strictly antigen dependent, we show that NKG2C/E can costimulate the cytotoxic activity of ThCTL in vivo, since target cells lacking the ability to present peptide on Qa-1b, which binds to NKG2C/E, are significantly protected from lysis by ThCTL during IAV infection. The ThCTL express a unique pattern of molecules including high levels of granzyme B, PSGL-1, PD-1 and CD27 as well as transcription factors Eomes and Blimp-1. We find that Blimp-1 is critical for the generation and differentiation of this subset, since a CD4 T cell intrinsic defect in Blimp-1 leads to a broad reduction of most of the ThCTL program including cytotoxic activity and migration to the lungs as well as expression of NKG2C/E, granzyme B, PSGL-1 and CD27. These features help to define a distinct ThCTL cell subset generated under distinct conditions during an acute viral infection that has novel target specificity and thus likely occupies a unique functional niche.